ERBB SIGNALING IN LIVER ONTOGENY AND REGENERATION

肝脏个体发育和再生中的 ERBB 信号传导

• 批准号: 6177595
• 负责人: WILLIAM E RUSSELL
• 金额: $ 21.11万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177595
• 关键词: age difference; autoradiography; biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; diethylnitrosamine; embryo /fetus tissue /cell culture; epidermal growth factor; gene expression; genetically modified animals; growth factor receptors; hepatectomy; histogenesis; laboratory mouse; laboratory rat; liver metabolism; liver regeneration; protooncogene; tissue /cell culture

Our long term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of liver. Epidermal growth factor (EGF) and its homologs are arguably the most thoroughly-studied growth factors in the control of liver growth, regeneration, and carcinogenesis, but we now know that signaling through the EGF receptor (EGFr) involves its interaction with a family of related receptors, the ErbB proteins. This study focuses on the role played by the ErbB receptors as regulators of growth and differentiation in liver. ErbB interactions have been studied almost exclusively in transformed or genetically altered cells in culture; their relevance to normal biology outside of the central nervous system and cancer cells has been unclear. We believe this proposal to represent a major conceptual reassessment in how EGF and its related growth factors function in one of its most prominent target tissues. We have documented extensive interactions between the EGFr and ErbB2 and ErbB3, but while the EGFr and ErbB3 are continuously expressed during liver development, the hepatic expression of ErbB2 is extinguished postnatally. The aims of this proposal are to: 1. Define the developmental role of ErbB2 in designating the proliferative or differentiative phenotype of fetal liver; 2. Delineate the ErbB signaling mechanisms that distinguish fetal from adult liver; and 3. To establish the role of ErbB signaling in liver regeneration. Progress toward these aims will improve our understanding of how EGF- like molecules signal in a normal tissue, how the liver differentiates into its adult functional form, and the role of these potent mitogens in regulating the dramatic restoration of liver grwoth during regeneration. Liver regeneration is a paradigm for other conditions of normal or altered growth regulation, including tissue hypertrophy, wound healing, cancer, and possibly even normal childhood growth. In addition to elucidating mechanisms of growth control in the liver, our studies may ultimately aid in the generation of mature hepatocytes from undifferentiated precursor cells for transplantation and for generation of artificial livers.

我们的长期目标是了解控制的机制 肝脏的生长，分化和再生。表皮生长 因素（EGF）及其同源物可以说是最彻底研究的 控制肝脏生长，再生和 癌变，但我们现在知道通过EGF受体发出信号 （egfr）涉及与相关受体家族的相互作用， ERBB蛋白。 这项研究的重点是ERBB的作用 受体作为肝脏生长和分化的调节剂。 ERBB 相互作用几乎仅在转换或 培养中的基因细胞改变；它们与正常生物学的相关性 中枢神经系统和癌细胞之外尚不清楚。 我们相信这一建议代表重大概念重新评估 在EGF及其相关的增长因素如何在其最多的一种中起作用 突出的靶组织。 我们已经记录了广泛的互动 在EGFR和ERBB2和ERBB3之间，但是EGFR和ERBB3是 在肝发育过程中连续表达肝表达 ERBB2的出现在产后熄灭。 该提案的目的是： 1。定义ERBB2在指定 胎儿肝脏的增殖或分化表型； 2。描绘 将胎儿与成人肝脏区分开的ERBB信号传导机制； 和3。确定ERBB信号在肝脏再生中的作用。 朝着这些目标的进步将提高我们对EGF-的理解 像分子在正常组织中信号一样，肝脏如何区分 进入其成人功能形式，以及这些有效的有丝分裂剂的作用 在调节肝脏的戏剧性恢复时 再生。 肝脏再生是其他条件的范式 正常或改变生长调节，包括组织肥大，伤口 康复，癌症，甚至可能正常的儿童生长。 此外 为了阐明肝脏生长控制机制，我们的研究 最终可能有助于产生成熟的肝细胞 未分化的前体细胞进行移植和生成 人造肝。